Synthetic oestrogens



Patented June 11, 1946 UNITED STATES PATENT 1 OFFICE SYNTHETIC OESTROGEN S Morris S. Kharasch, Chicago, Ill., asslgnor to Eli Lilly and Company, Indianapolis, Ind., a corporation of Indiana No Drawing; Application November 13, 1943, Serial No. 510,217

5 Claims.

This application is a continuation in .part apyield of product and relatively rare raw materials.

This invention has, as an object, the preparation of oestrogens in improved yield. Another object is to prepare oestrogens from readily available raw materials. Still another object is new intermediates for the preparation of oestrogens, and a method of producing the same. Other object will become more apparent hereinafter.

It has now been discovered that new intermediates for stilboestrol and hexoestrol can be made from anethole and similar compounds, and that these oestrogens can be easily prepared from such intermediates. By way of illustration, the process will be discussed with regard to anethole as the starting material, the scope of the invention being more fully set forth hereinafter. The chemistry of the process is as follows: Anethole is halogenated with dry hydrogen bromide to anethole hydrobromide, thus:

1 cmoOcn=on-orn HBr cmoGi-cHr-om Anethole hydrobromide is reacted with excess 4 sodamide in liquid ammonia to produce a product having the empirical formula CaoHmOz, thus:

I (2) CHfl-O-E-CHa-CH: NaNH:

CzoHuO: ZNaBr NH:

The product having the empirical formula C2oH24O2 noted in Equation 2 is a new compound. It has two p-methoxyphenyl groups and a melting point of 120.5" C. (corrected). The new product is not p,p'-dimethoxy-3,4-diphenyl-3- hexene, but yields stilboestrol upon subsequent treatment to be hereinafter described. Moreover, it is not the isomer described by Wessely and Kleedorfer [Naturwiss., 2'7, 567 (1939)]; for one form of the isomer so described is an oil. while the other is a solid melting at 50 C. Accordingly the composition obtained by the reaction outlined in Equation 2 may be represented by 1 either of the following formulas:

H H (a) magi-(00m H2} lzHl 5 ("3H:

two racemic pairs p,p'-dimethoxy-3,4-diphenyl-l-hexene A! H: l-metby1-2,3-di-(p-methoxyphenyl)-3-ethylcyclopropane When this new product having the melting point of 120.5 C. is demethylated, the double bond shifts and stilboestrol is formed, thus:

KOH

ACHiOH-CHiOH CIIA I Moreover, when the new product having the melting point of 120.5 C. is hydrogenated, the dimethyl ether of hexoestrol is formed, thus:

0 (6) CaoHnO: H! v CiHl H CEQO& B OOCH. 5 (E211:

This ether can be demethylatedto yield hexoestrol, which also has potent oestrogenic properties, thus:

C!H| H I K ii A A ACHzOH-CHaOH H 55. IG

The process will now be described in detail, it

accaoce 3 being understood that this description is merely by way of illustration and that suitable changes may be made as will become more apparent hereinafter.

Example 1 Three tenths mole of anethole diluted with 2V2 times its volume of a dry hydrocarbon solvent, preferably toluene, is caused to absorb .3 mole of dry hydrogen bromide. This operation is conducted at -15 to -20 C. Lower temperatures (80 C.) may be used but they'offer no great "advantages over the temperatures of -15 to and is identified as hexoestrol by the fact that it 20 c. At the completion of the reaction, the 3 mixture is allowed to rise to 0 C. and a stream of an inert gas (CO: or N2) is bubbled through it to displace any excess of hydrogen bromide. The mixture is then degassed by evacuation with a water pump. The solution is then cooled again and maintained at 80 C. until used.

This solution of anethole hydrobromide is added in small portions to a vigorously agitated solution-suspension of 40 parts (three moles) of sodamide in about 700 parts of liquid ammonia. The following color changes ensue: the mixture is a yellow-green after the first addition and becomes a deep red in a few minutes; each subsequent addition discharges the color and the same sequence again ensues. After all the organic reactant has been added and the reaction has gone to completion, as evidenced by the return of the deep red color, the ammonia is evaporated and the residue is taken up in water, acidified, and extracted with ethyl acetate until the extracts are colorless. The ethyl acetate-solution is dried and filtered, and the ethyl acetate is removed by distillation at reduced pressure. The residual oil is dissolved in methanol, whereupon a separation of crystalline material is obtained. This crystalline material is the product which has the empirical formula C20H24O2 and which has two p-methoxyphenyl groups as heretofore described. The total yield of this product is 1'? parts or 34 percent of the theoretical. Fourteen (14) parts of purified product melting at 118 C. is recovered after recrystallization from methanol. A small did not lower the melting point of the authentic sample of that material prepared by well established methods. The yield of this material is nearly quantitative.

Example 4 Two (2) parts of the product having the empirical formula C2oH2402 obtained as described in Example 1, 5 parts of KOH, and 30 parts of ethylene glycol are sealed in a heavy pyrex bomb tube and heated at 224 C. for 18 hours. The resultant mixture is diluted with water, filtered to remove silica and acidified. The milky solution thus formed is digested for a short time on a steam bath, cooled, and the solid which separates is collected on a filter. By recrystallization from benzene, the crude product is separated into an oil and a solid. The latter is identified as stilboestrol after several recrystallizations--yield 0.9 part. The residual oil, when treated at 224 C. with 1.5 parts of KOH in 8 parts of ethylene glycol in a sealed tube as above, gives an additional 0.1 part of solid.

While the invention has been specifically described with reference to anethole, it is not limited thereto. Since the methyl radical of the alkoxy group in this compound is inactive during hydrohalogenation and during reaction with sodamide, it may be replaced by other alkyl radicals without materially affecting such reactions.

sample purified by many recrystallizations melts at 120.5 C. (corrected), whose properties and absorption spectra indicate the structure of p,pdimethoxy-3,4-diphenyl-hexene-1 or l-methyl- 2,3-di-(p methoxyphenyl) -3-ethylcyclopropane. The residue from the reaction was mainly composed of polymerized anethole and high-boiling oils.

Example 2 A measured quantity of the product having the empirical formula Casi-12402, obtained as described in Example 1 and dissolved in methanol,

Example 3 Two (2) parts of hexoestrol dimethyl ether, 3 parts of KOH, and 30 parts of ethylene glycol are sealed in a heavy pyrex bomb tube and heated at 242 C. for 12 to 18 hours. The resulting mixture is diluted, the water filtered to remove silica,

i Hi? CeHu CH2 Two racemic pairs D1P'-dialkoxy-3,4-diphenyl-l-hexene ROCg-COR l-inethyl-2,3-di(p-alkoxyphenyl)-3-ethyleyclopropane in which R. is an alkoxy group. In either case,

the alkoxy groups are converted to hydroxy groups to produce the oestrogen.- Moreover, other oestrogens can be prepared by the use of compounds having more than one alkoxy group. Furthermore, the CI- I=CH-Cm-group of the raw material can be replaced by other hydrocarbon groups containing the double bond in the same position. In general, suitable raw materials are compounds of the formula CH=R wherein R is an alkylidene radical of from 2 to 6 carbon atoms, R1 is an alkoxy radical of from 1 .and alkaline-earth metals are suitable.

While hydrohalogenation is preferably carried out with hydrogen bromide, as illustrated, both hydrogen chloride and hydrogen iodide can be used under suitable conditions. One must always bear in mind the fact that the unsaturated compounds are polymerized by halogen acids. For that reason, it is desirable to carry out the addition of the halogen acids under such conditions where such polymerization will be at a minimum. Such conditions might involve the addition of th halogen acid in solvents other than hydrocarbon solvents; for instance, dihexane may be conveniently used as a solvent in many cases.

While sodamide is preferred for the condensation step, other ammonia soluble amides may be used, such, for example, as potassium amide or calcium amide. In general, the amides of alkali The amide must be present in excess to obtain a good yield, and, preferably, there should be present at least three mole equivalents of the amide for each mole equivalent of the compound to be condensed. For these two reasons, it is desirable to add the hydrohalide addition product dissolved in a suitable solvent, such as toluene, to the alkali amides dissolved in liquid ammonia rather than that used in the first procedure.

This step may be carried out at any desired temperature below the critical temperature of ammonia, suitable pressure being used to keep the ammonia in the liquid state. However, high temperatures and pressure are less desirable than 'low temperatures (below -35 C.) and atmospheric pressure due to the fact that high temperatures promote the formation of by-products. The amount of 1iquid ammonia should be sufficient to form a solution of the amide, but is not critical.

The hydrogenation of the product having the empirical formula Gaol-I240: may be varied in wide limits from the exact procedure set forth in Example 2. Thus, instead of methanol as a solvent, ethanol or glacial acetic acid or other polar solvents may be used. Furthermore, instead of platinum black as a catalyst, Raney nickel or paladium black on barium sulfate or asbestos may be employed. Other known mild hydrogenation catalysts gave equally satisfactory results. The temperature and pressure during hydrogenation may be varied considerably without hydrogenatms the double bonds of the benzene ring. How- 6 ever, high pressures and high temperatures should be avoided.

In Examples 3 and 4, a specific procedure has been disclosed for demethylating the alkoxy compounds to hexoestrol and stilboestrol. However, these conditions may also be varied over a wide range within the limits. Thus, instead of ethylene glycol other high boiling polar liquids may be employed; for instance, glycerin or trimethylene glycol. The temperature of the reaction may also be varied. Thus, it is possible to demethylate using a temperature of 200 0., although a longer period of time is then necessary. However, it is not desirable to carry out the demethylation temperatures higher than 250 C. for considerable decomposition takes place at those temperatures. Instead of potassium hydroxide as the alkali, sodium hydroxide may be used, although the former reagent is preferable.

It is apparent that many widely different embodiments of this invention may be made without departing from the spirit and scope thereof, and, therefore, it is not intended to be limited except as indicated in the appended claims.

What is claimed is:

l. The method of preparing a synthetic estrogen which comprises reacting an excess of an alkali amide, dissolved in liquid ammonia, with a halomethane of the class consisting of 4-alkoxyphenylalkylhalomethanes wherein the alkoxy groups have from 1 to 4 carbon atoms and the alkyl groups have from 2 to 6' carbon atoms and wherein the halogen is of the group consisting of chlorine and bromine, and reacting the resulting intermediate product with a strong alkali at elevated temperature whereby the alkyl groups are removed from the alkoxy groups and .the saturated carbon-to-carbon linkage of the ethane group joining the phenyl groups is converted to an olefine linkage.

2. The method of preparing a synthetic estrogen which comprises reacting anethole hydrobromide with an excess of sodamide, dissolved in liquid ammonia, to produce a compound having the empirical formula C2oH24O2, two p-methoxyphenyl groups and a melting point of 120.5 C., and reacting this product with a strong alkali at elevated temperature whereby the methyl groups are removed from the methoxy groups and the saturated carbon-to-carbon linkage of the ethane group is-converted to an oleflne linkage, and stilboestrol is formed.

3. In the method of preparing a synthetic estrogen, the step which comprises reacting an excess of an alkali amide, dissolved in liquid ammonia, with a halomethane of the class consisting of 4-alkoxyphenylalkylhalomethanes wherein the alkoxy groups have from 1 to 4 carbon atoms and the alkyl groups have from 2 to 6 carbon atoms, and wherein the halogen is of the group consisting of chlorine and bromine.

4. In the method of preparing a synthetic estrogen, the step which comprises reacting anethole hydrohalide wherein the halogen is of the group consisting of chlorine and bromine, with an excess of sodamide dissolved in liquid ammonia.

5. In the process of preparing a synthetic estrogen, the step which comprises reacting a compound having the empirical formula CmHuOa, two p-methoxyphenyl groups and a melting point of 120.5 C. with a strong alkali at elevated temperature to form stilboestrol.

uoaars e. 

